Nanoparticle chains and Preparation Thereof

ABSTRACT

Fabrication and arrangement of nanoparticles into one-dimensional linear chains is achieved by successive chemical reactions, each reaction adding one or more nanoparticles by building onto exposed, unprotected linker functionalities. Optionally, protecting groups may be used to control and organize growth. Nanoparticle spheres are functionalized in a controlled manner in order to enable covalent linkages. Functionalization of nanoparticles is accomplished by either ligand exchange or chemical modification of the terminal functional groups of the capping ligand. Nanoparticle chains are obtained by a variety of connectivity modes such as direct coupling, use of linker molecules, and use of linear polymeric templates. In particular, a versatile building block system is obtained through controlled monofunctionalization of nanoparticles.

RELATED APPLICATIONS

This application is a divisional application of co-pending U.S. patentapplication Ser. No. 10/621,790, filed Jul. 17, 2003, now U.S. Pat. No.7,476,442, which claims the benefit of U.S. Provisional Application Ser.No. 60/396,337, filed Jul. 17, 2002, the entire disclosures of which areeach herein incorporated by reference.

FIELD OF THE INVENTION

This invention relates to synthesis of nanoparticles and theirassemblies and, in particular, to controlled synthesis of functionalizednanoparticles, nanoparticle assemblies, and nanoparticle chains.

BACKGROUND

Inorganic nanoparticles, nanoclusters, and colloids have become asubject of intensive research and offer a great many potential uses iftheir size, ligand sphere, and positioning can be reliably controlled(Shipway A. N. et al., Chem Phys Chem. 1: 18-52 (2000)). A variety ofdevices can be envisioned, ranging from specialized nanosensors tomolecular electronics and nanoscale optical devices. Many suchapplications are not presently practical due to the lack of appropriatemethods for synthesis of nanoparticle chains and for fabrication ofnanoparticle chains into a circuit.

Numerous approaches to synthesis of nanoparticles exist, includingpyrolysis of organometallic precursors, arrested precipitation,precipitation in reverse micelles, and exchange (metathesis) reactions.Because nanoparticle properties depend strongly on size, shape,crystallinity, and surface derivatization, the particle synthesis isnormally tailored to control these parameters for a particularapplication. In general, if the nanoparticles are intended to beutilized in their native particulate state without any fusion into bulkmaterial (agglomeration), then any synthetic method yielding appropriatesize control and crystallinity may be utilized (Jacobson et al, U.S.Pat. No. 6,294,401 (2001)).

Because of this, current synthetic methods for nanoparticles are largelyconcerned with obtaining size control and a viable synthesis of thedesired compound (Schmid et al., Adv. Mater. 10: 515-526 (1998)).Syntheses have been designed to incorporate ligands with supramolecularfunctionality, with the aim of connecting one nanoparticle to anothermolecular entity or nanoparticle (Loweth et al., Angew. Chem. Int. Ed.38, 1808-1812 (1999); Boal et al., J. Amer. Chem. Soc. 122: 734 (2000);Liu et al., Adv. Mater. 12: 1381-1383 (2000); Mann et al., Adv. Mater.12: 147 (2000); Novak et al., J. Amer. Chem. Soc. 122: 3979-3980(2000)). For example, monofunctional gold nanoparticles have beenproduced by statistical ligand exchange reactions, which is a verydifficult task requiring subsequent extensive purification andseparation steps, such as high-performance liquid chromatography (U.S.Pat. No. 5,360,895, Hainfeld et al. (1994), U.S. Pat. No. 5,521,289,Hainfield et al. (1996), U.S. Pat. No. 6,121,425, Hainfield et al.(2000)).

Biological techniques have been found to be useful in directingsynthesis of inorganic materials (Storhoff et al., Chem. Rev. 99:1849-1862 (1999); Lee et al., Science, 296, 892-895 (2002)). The realmof biology offers examples of both controlled nanoparticle synthesis andthe building of elaborate functional structures by the use of polymers.For example, ferritin is a cage-like nanoparticle of a specific sizethat can be synthesized in a controlled fashion. Ferritin and similarstructures have been used in the synthesis of nanoparticles ofwell-controlled size (Mukherjee et al., Angew. Chem. Int. Ed. 40: 3585(2001); Shenton et al., Angew. Chem. Int. Ed. 40: 442-445 (2001)).Biology also offers a number of diverse processes that can be carriedout by polymeric chains such as, for example, peptide and nucleotidechains. Attempts have also been made to utilize biological motifs tocontrol the relative positioning of nanoparticles (Lee et al., Science,296, 892-895 (2002)).

Nanoparticles fall into two general categories: charge-stabilizedcolloids and ‘molecularly’ soluble colloids/chemical entities.Charge-stabilized colloids are typically synthesized in polar media.Although charge-stabilized colloids are thermodynamically unstable dueto high surface energy, they maintain their small size by electrostaticrepulsion. Kinetically, charge-stabilized colloids are very unlikely toagglomerate.

Agglomeration of molecularly soluble nanoparticles can typically beavoided by modifying the entropy, solvation energy, and/or stericshielding of the nanoparticles. These modifications are generallyaccomplished by the use of organic ligands, which allows fine-tuning ofsolubility for various solvents. The bond strength of the ligands to ananoparticle typically varies from low strength Lewis acid—Lewis baseinteractions to higher-strength covalent bonds.

Most ligands are quite mobile within the ligand sphere of a nanoparticleand can migrate from one side of a nanoparticle to another. Therefore,while two ligands may be on opposite sides of a nanop article initially,they can migrate to the same side of the particle over time, especiallywhen there is an attractive interaction (Boal et al., J. Amer. Chem.Soc. 122: 734 (2000). Migration of ligands can interfere with buildingcomplex supramolecular structures out of nanoparticles. Further, becausethe ligand sphere is not rigid, the ligand-particle-ligand ‘bond angle’is not fixed for any two ligands on the particle. As a result, theligands are free to move around, which can destroy the desiredsupramolecular effect.

What has been needed, therefore, are generalized coupling chemistriesthat allow buildup of arbitrary chains of nanoparticles in a polymericfashion. Methods of nanoparticle synthesis are therefore needed thatallow for the reliable incorporation into the nanoparticle ligand sphereof functionality through specifically designed chemically reactivesites.

SUMMARY

These and other objectives are met by the present invention, whichrelates to the creation of polymers and other supramolecular structurescontaining nanoparticles. Using the present invention, nanoparticles areincorporated into the structure when the polymer chain is synthesized,rather than as a post-polymerization modification. In the method of thepresent invention, nanoparticles are assembled into structures bysuccessive chemical reactions, with each reaction adding one or morenanoparticles by building onto exposed, unprotected linkerfunctionalities. Protecting groups may optionally be used to control andorganize growth.

In one aspect, the invention is a method for functionalization ofnanoparticles in a controlled fashion. Chemical properties ofnanoparticles are modified by monodentate ligands, normally used in thesynthesis of nanoparticle precursors, and/or by ligands that arecustomized to include a functional group utilized for linking chemistryin nanoparticle assembly. In particular, a versatile building blocksystem is obtained through controlled monofunctionalization ofnanoparticles.

A preferred embodiment of the invention relies upon capture of amonofunctionalized nanoparticle ligand shell by initiation ofpolymerization. The ligand exchange reaction takes place throughaddition of a new ligand, followed by dissociation of an old ligand. Theligand shell is thereby captured in a monofunctionalized state. As soonas the new ligand enters the ligand shell of the nanoparticle, itinitiates a polymerization reaction that involves the whole of theligand shell, preventing further ligand exchange processes fromoccurring.

In another aspect, the invention features structures and syntheses offamilies of linker ligands useful in the stepwise assembly ofnanoparticle structures. In one embodiment, the linker ligands havemultiple arms terminating either in chemical functionalities that anchorthe ligand to the surface of a nanop article or in linker functionalitythat is used to link up nanoparticles into chains or other structures.

In yet another aspect, the present invention features structures andsyntheses of the nanoparticle/linker ligand building blocks. In oneembodiment, nanoparticle precursors, mixtures of ligands, and linkermoiety precursors are directly used in the synthesis. The size of thenanoparticles may be optionally controlled and stabilized by usingwrapping linker moieties. Synthesis may alternatively be accomplished byeither ligand exchange reactions in solution or capture of gas phaseparticles, using the linker moieties. In any of these syntheses, thenumber of linking ligands per nanoparticle is crucial, and can becontrolled by varying synthetic conditions and/or by a number ofpurification means.

In yet another aspect, the invention features syntheses of polymersthrough using nanoparticle/linker building blocks (e.g., chains ofnanoparticles). In one embodiment, synthesis of polymeric chains isaccomplished by using stepwise polymerization reactions with appropriatelinker moieties, akin to oligopeptide synthesis. The synthesis mayalternatively utilize chain polymerization reactions by choosingappropriate linker moieties that are used for peptide linkage.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates one possible linker geometry according to thepresent invention, having symmetrically spaced linking groups arrangedaround arbitrary nanoparticle building blocks;

FIG. 1B illustrates another possible linker geometry according to thepresent invention, having diverse chemical moieties that can formcovalent bonds with suitable partner functionalities linked aroundarbitrary nanoparticle building blocks;

FIG. 2A depicts one structure of supramolecular nanoparticles that maybe formed from nanoparticle building blocks according to the presentinvention, a linear oligomeric chain containing one specificnanoparticle building block;

FIG. 2B depicts an oligomeric chain having alternating nanoparticletypes;

FIG. 2C depicts an oligomeric chain having three alternatingnanoparticle types;

FIG. 2D depicts an oligomeric chain having a defined sequence ofnanoparticle types;

FIG. 2E depicts a nanoparticle assembly having trigonal and tetragonalbuilding blocks;

FIG. 3 depicts a disubstituted nanoparticle having two terminalcarboxylate groups pointing in opposite directions that may form acovalent bond;

FIG. 4A depicts a class of nanoparticle chain system consisting of apreexisting oligo- or polymer template and nanoparticles havinguniformly spaced functional linking groups;

FIG. 4B shows that attachment of nanoparticles on the polymer may beachieved by ligand exchange leading to direct bonding of the linkerfunctional arm and the nanoparticle core;

FIG. 4C depicts an alternate method, covalent linkage between the linkerfunctional arm and the functionalized nanoparticle;

FIG. 5A depicts oligo- or polymerization of monofunctionalizednanoparticles according to the present invention, having nanoparticlebuilding blocks directly coupling to one another at preexistingmonofunctionalized oligomeric moieties;

FIG. 5B depicts an alternative oligo- or polymerization ofmonofunctionalized nanoparticles according to the present invention,having nanoparticle building blocks alternatively coupling through useof a small linking functional group;

FIG. 6 depicts two exemplary components of a system according to thepresent invention for producing monofunctionalized nanoparticles by‘capturing’ of the monofunctionalized ligand sphere through apolymerization mechanism;

FIG. 7A depicts two exemplary ligand structures that may be used inpractice of the present invention for wrapping a gold nanoparticle andproviding the functionality necessary for linking particles together;

FIG. 7B depicts an exemplary synthetic scheme leading to two examplemolecules used for creating a bifunctional nanoparticle that may beemployed in practice of the present invention;

FIG. 8 depicts a generic carbocycle moiety utilizable in the presentinvention for the core of the ligand structure, having variousattachment points;

FIG. 9 depicts the generic structure of a chelating arm of a ligand thatmay be employed in practice of the present invention;

FIG. 10 depicts the generic structure of a linking arm of a ligand thatmay be employed in practice of the present invention;

FIG. 11 depicts the B-cyclodextrin structure and the dimensions of threecommercially available cyclodextrins;

FIG. 12 depicts a linker structure according to the present invention,involving the linking of two cyclodextrin structures using host-guestchemistry;

FIG. 13 depicts two cyclodextrins bound to a nanoparticle and linkersaccording to the present invention;

FIG. 14 depicts a cyclodextrin cage that can control nanoparticle sizeand linker geometry according to the present invention; and

FIG. 15 depicts a cyclodextrin rotaxane designed to act as a spacerwithin the ligand sphere of a particle according to the presentinvention.

DETAILED DESCRIPTION

The present invention relates to the creation of polymers and othersupramolecular structures containing nanoparticles and nanoclusters.Using the present invention, nanoparticles are incorporated into thestructure when the polymer chain is synthesized, rather than as apost-polymerization modification.

In one aspect, the present invention is a method for functionalizationof nanoparticles in a controlled fashion. Chemical properties ofnanoparticles are modified by a set of ligands composed of monodentateligands, normally used in synthesis of nanoparticle precursors, andligands customized to have a functional group utilized for linkingchemistry in nanoparticle assembly. In certain applications, only linkerligands are used. Typically, use of only one, or possibly only a few,linker ligands is preferred on each nanoparticle or nanocluster,allowing for spatial and geometric control over the orientations of thelinker moieties. Alternatively, a single large ligand designed topresent several linker moieties at spatially separate locations on theligand sphere can be used.

In another aspect, the present invention features structures andsyntheses of families of linker ligands useful in the stepwise assemblyof nanoparticle structures. In one embodiment, the linker ligands havemultiple arms terminating in chemical functionalities, such as chelatinggroups, which anchor a ligand to the surface of a nanoparticle. One ormore arms may alternatively terminate in linker functionality, which isused to link up nanoparticles into chains or other structures byreaction with linker groups bound to other nanoparticles. If desired,the linker ligands may have chiral centers.

In yet another aspect, the present invention features structures andsyntheses of nanoparticle/linker ligand building blocks. In oneembodiment, nanoparticle precursors, mixtures of ligands, and linkermoiety precursors are directly used in the synthesis. The size of thenanoparticles may optionally be controlled and stabilized by usingwrapping linker moieties. These nanoparticles can then be used to buildnanoparticle structures as described herein. Synthesis may alternativelybe accomplished by ligand exchange reactions in solution or by captureof gas phase particles, using the linker moieties. In any of thesesyntheses, the number of linking ligands per nanoparticle is crucial,and can be controlled by varying the synthetic conditions and/or by anumber of purification means including, but not limited to,precipitation, chromatography, centrifugation, extraction,crystallization, and titration.

In yet another aspect, the present invention features syntheses ofpolymers by using nanoparticle/linker building blocks (e.g., chains ofnanoparticles). In part, this invention mimics the functionality ofbiological processes in nanoparticle assembly. In one embodiment,synthesis of polymeric chains is accomplished by using stepwisepolymerization reactions with appropriate linker moieties, akin tooligopeptide synthesis. The synthesis may alternatively employ chainpolymerization reactions by choosing appropriate linker moieties, suchas terminal amino acid groups, that are used for peptide linkage.

In the method of the present invention, nanoparticles are assembled bysuccessive chemical reactions, each reaction adding one or morenanoparticles by building onto exposed, unprotected linkerfunctionalities. Optionally, protecting groups may be used to controland organize growth. This approach allows for a greater diversity ofstructures to be built. In order to produce nanoparticle assemblies withchirality, the linker arms may themselves be chiral. This overallapproach may further be used in conjunction with solid-phase techniques,resembling certain methods of synthesizing of oligonucleotides oroligopeptides.

Overview. A preferred embodiment of the invention involves controlledplacement, with fixed geometry, of linking groups around a nanoparticle.Each linking group may optionally have a different functionalreactivity, rendering the linking moieties chemically non-interferingand allowing the resulting nanoparticle building block to maintainversatility. Also preferably, each linking group is equidistant from thesurface of the nanoparticle. The size of the nanoparticle may optionallybe controlled by linker ligands, either during synthesis or afterwards.The linker ligands employed are preferably compatible with a widevariety of nanoparticle elemental compositions.

FIGS. 1A and 1B illustrate some of the variety of possible linkergeometries and a number of linking groups, such as linker ligands,around arbitrary nanoparticle building blocks 120. Nanoparticle buildingblocks 120 are shown as spherical only for convenience; they may takeany other three-dimensional shape. For example, triangles, rods, cubes,vertex-truncated cubes, and tripods are rare, but occasionallyoccurring, shapes for nanoparticles. The sizes of the linking groups areexaggerated in FIGS. 1A and 1B in order to illustrate potentialstereochemistries around the particle.

Any number of distinct linkers may fill the role of linking group. Forexample, supramolecular structures may be built in a controlled fashionby use of chemically orthogonal linking groups. Controlled chaincatenation may also be achieved through the use of different protectinggroup functionalities, which may be selectively (and separately) removedor deactivated. Use of these and similar procedures allows synthesis ofa diverse set of structures.

In FIG. 1A, nanoparticles 120 have been treated with only one specificfunctional ligand, resulting in symmetrically spaced linking groups 130.Mono- to multifunctionalization of the ligand sphere can be achieved bystoichiometric ligand exchange reaction of an inert nanoparticle. On theother hand, as shown in FIG. 1B, diverse chemical moieties 130, 140,150, 160 can form covalent bonds with suitable partner functionalities.For example, amide linkages can be formed when a nanoparticle has bothcarboxylate and amine functional groups. Under amide bond formingconditions, other functional groups are preferably inert and may be, forexample, Heck coupling partners.

FIGS. 2A to 2E depict several exemplary structures of supramolecularnanoparticles that may be formed from the building blocks shown in FIGS.1A and 1B. Any of the various possible connections may be made betweenthe nanoparticles. FIGS. 2A to 2D depict several of the possible kindsof linear oligomeric chains containing nanoparticles of a definedlength. The chains may also be a polydisperse polymer formed by either astandard step-growth or chain-growth type polymerization the two typesof polymerization mechanisms by which all polymers are formed. FIG. 2Adepicts the simplest chain system, having one specific nanoparticlebuilding block 202 in which the connection is made through directcoupling 204. FIG. 2B depicts an oligomer with alternating nanoparticletypes 202, 210. FIG. 2C depicts an oligomer with three alternatingnanoparticle types 202, 210, 212. FIG. 2D depicts an oligomer with adefined sequence of nanoparticle types 202, 210, 212. Anoligomer/polymer of random sequence may also be synthesized from thesame building blocks. FIG. 2E depicts an example of a more elaboratestructure using trigonal 220 and tetragonal 230 building blocks.

In one specific embodiment, the nanoparticles depicted in FIG. 1A arereadily treated by one-step ligand exchange in order to generate highersymmetry. While the degree of complexity per nanoparticle of FIG. 1A islower than for those depicted in FIG. 1B, synthetic effort is minimized,and they are obtainable by a straightforward method. To accomplish achain-forming reaction using these nanoparticles, another molecularlinker component is used. For example, as shown in FIG. 3, adisubstituted nanoparticle 310 having two terminal carboxylate groups320 pointing in opposite directions may form a covalent bond with asymmetrical diamine 330 such as, for example, ethylenediamine.

Another possible class of nanoparticle chain system consists of apreexisting oligo- or polymer template and nanoparticles, as shown inFIGS. 4A to 4C.

FIG. 4A illustrates a schematic linear polymer chain 405 containinguniformly spaced functional linking groups 410. The polymer 405 isgenerally required to be of sufficiently large molecular weight comparedto the nanoparticles to allow the stoichiometry to be preciselycontrolled. Moreover, the branching functional arms 410 should be spaceda sufficiently large distance between the two adjacent groups. Forexample, to accommodate gold nanoparticles sized 1.5-2 nm evenly throughone ligation per particle, the functional arm distances should begreater than 2 nm. The loading level of the functional groups on thepolymer chain can be controlled by any of the well-known methods in theart.

FIG. 4B shows that attachment of nanoparticles 420 on the polymer 405may be achieved by ligand exchange leading to a direct bonding of thefunctional arm 410 and the nanoparticle core. Covalent linkage betweenthe arm 410 and monofunctionalized nanoparticle 420 is an alternativemethod, as shown in FIG. 4C. For example, if the arms on the polymerhave a terminal amine, they can be linked to monocarboxylic acid onnanoparticles. In this case, the functional arm spacing is lessimportant, due to the fact that the availability of covalent linkage pernanoparticle is only one (Harth et al., J. Amer. Chem. Soc. 124:8653-8660 (2002); Boal et al., Nature 404: 746-748 (2000); Boal et al.,Adv. Functional Mat. 11(6): 461-465 (2001).

Functionalization of nanoparticles. In one aspect, the invention is amethod for assembly of nanoparticles in a controlled fashion. Chemicalproperties of nanoparticles are modified by a set of ligands, and theresulting nanoparticle building blocks are then assembled by successivechemical reactions, with each reaction adding one or more particles bybuilding onto exposed, unprotected linker functionalities. Protectinggroup chemistry may optionally be employed in order to provide addedversatility in the structures that can be built. In particular, severalkinds of orthogonal linker chemistries may be employed in the samesystem, allowing a greater diversity of structures to be built. In someembodiments, the invention may use chiral linker arms to producenanoparticle assemblies with chirality and/or more elaborate structures.

In one implementation, the method utilizes solubilization ofnanoparticles by lyophilic ligand spheres using any suitable methodologyknown in the art (but typically not by electrostatic mechanisms).Solubility of nanoparticles in various solvent media having a largerange of polarities is subject to completely controllable modulation.For instance, classical gold nanoparticles protected by a normalalkanethiolate monolayer are generally soluble in non-polar organicsolvents such as n-alkanes, toluene, THF, and diethyl ether (Brust etal., J. Chem. Soc. Chem. Commun. 801 (1994)). Displacing of thisalkanethiolate monolayer with hydrophilic functional group-terminatingthiols produces water-soluble nanoparticle systems (Simard, J., J. Chem.Soc. Chem. Commun. 1943 (2000)).

The invention includes structures and synthesis of families of linkerligands useful in the stepwise assembly of nanoparticle structures. Eachfamily of linker ligands is based upon a specific linker group, such asa carboxylic acid or amine. The members of each family are designed fordistinct nanoparticle elemental compositions. For example, nanoparticleelemental compositions may include Au, Ag, Pt, Ti, Al, Si, Ge, Cu, Cr,W, Fe, and their corresponding oxides. In addition, group III-V andII-VI semiconductors, such as CdSe, CdS, CdTe, and GaAs, can be used toprepare nanoparticles. In some embodiments, the invention may bepracticed in conjunction with solid-phase techniques, in a mannerresembling the methods by which oligonucleotides or oligopeptides arebuilt up.

In one embodiment, the linker ligands have multiple arms terminating inchemical functionalities, such as chelating groups, tailored for thespecific nanoparticle chemistry to be used to anchor the ligand to thesurface of the nanoparticle. One or more arms may additionally terminatein linker functionality, which is used to link nanoparticles into chainsor other structures by reaction with linker groups bound to othernanoparticles. If desired, the linker ligands may have chiral centers.

In one embodiment of the present invention, nanoparticle-branched chainsof the type depicted in FIGS. 4A to 4C are expanded by oligo- orpolymerization of monofunctionalized nanoparticles, as shown in FIGS. 5Aand B. Nanoparticle building blocks 510 in FIG. 5A directly couple toone another at preexisting monofunctionalized oligomeric moieties 520,530 that relieve steric hindrances. Alternatively, as shown in FIG. 5B,a versatile system employs a small linking functional group such as anamino acid. Sequential peptide synthesis using this monofunctionalizedamino acid-nanoparticle, in addition to the 20 natural amino acids, maybe used to produce an elaborate one-dimensional nanoparticle chainsystem.

Stoichiometric ligand exchange or chemical modification formonofunctionalized nanoparticles usually produces not only mono-, butalso di-, tri-, tetrafunctionalized nanoparticles, etc. A preparationand purification method for monofunctionalized gold particles has beenpreviously reported (See Hainfeld et al., U.S. Pat. Nos. 5,360,895;6,121,425 (1994; 2000)), but requires use of an extensive HPLCseparation technique that may present difficulties in identification ofthe number of activated functional groups by either spectroscopic ormicroscopic techniques. The process of Hainfeld et al also lowers theproduct yield significantly. In contrast, the present invention providesfacile purification and preparation methods that can reduce the effortrequired for purification.

By way of example, in one embodiment the mixture of mono- tomultifunctionalized nanoparticles is treated with a slight excess ofbridging linker molecules in order to make dimer, trimer and tetramernanoparticles. Because the resulting nanoparticle dimers and othernanoparticle aggregates have multiplicative molecular weights, thesedimentation equilibrium factors are changed and ultracentrifugationgenerates a sedimentation gradient that depends on the degree ofaggregation. Dimer species formed by two monofunctionalizednanoparticles can be physically separated and identified by electronmicroscopic technique such as transmission electron microscopy. Theseparated dimers are then subjected to a linkage breaking reaction inorder to release the monofunctionalized nanoparticles.

One embodiment of the method of the present invention, used formonofunctionalizing a nanoparticle, is shown in FIG. 6. This embodimentrelies upon capture of the monofunctionalized nanoparticle ligand shellby initiation of polymerization. The ligand exchange reaction takesplace by addition of a new ligand, followed by dissociation of an oldligand. The ligand shell is thereby captured in a monofunctionalizedstate. As soon as the new ligand enters the ligand shell of thenanoparticle, it initiates a polymerization reaction. Thispolymerization reaction involves the whole of the ligand shell,preventing further ligand exchange processes from occurring.

The rate of the ligand exchange reaction can be controlled viaconcentration, so that the polymerization reaction occurs much morequickly than the addition of a second ligand to the nanoparticle shell.In this way, more than one new ligand is not added before a ‘locking in’of the ligand shell structure. These new ligands contain at one terminusa linking moiety for further manipulation of the monofunctionalizednanoparticles. This method ensures the monofunctionalization of thenanoparticle ligand shell and does not involve extensive purification,making it particularly desirable.

FIG. 6 depicts two example components of a system designed to producemonofunctionalized nanoparticles 610 by ‘capturing’ of themonofunctionalized ligand sphere through a polymerization mechanism. Onecomponent is a metal or semiconducting nanoparticle 612 that has beensynthesized using ligand 614. The metals and semiconductors ofnanoparticle 612 could be, for instance, Au, Ag, Cu, Pt, Pd, Ir, CdS,ZnS, ZnO, CdSe, CdTe, or any other suitable material. Ligand 614contains several elements. A linking Lewis base moiety X 616 istypically necessary for nanoparticle formation, control of nanoparticlesize, and agglomeration prevention, providing for stabilization ofmetallic or semiconductor nanoparticle 612. Lewis base moiety X 616 isoften sulfur, though it can consist of atoms such as Se, Te, P(particularly semiconducting particles), N (particularly semiconductingparticles), or Lewis basic organic groups such as carboxylic acid.

Methylene spacers (methylene linking units) n 618 and m 620, locatedbefore and after a polymerizable moiety Z 622, help to form a reasonablemonolayer covering the nanoparticle and spatially provide a ‘hold-off’zone around the nanoparticle, providing it with kinetic stability andthereby preventing agglomeration. By way of example, the spacer length mand n could be 0-20 methylene units. Typically, the overall length of astabilizing ligand around a metal nanoparticle, such as ligand 614, is 1or more nanometers.

Polymerizable moiety Z 622 is designed to polymerize once a single‘polymerizing ligand’ is place-exchanged onto the ligand shellsurrounding nanoparticle 612. The polymerization reaction locks theligand shell into place around the nanoparticle, stabilizing it andpreventing further ligand exchange. Thus, once a single polymerizingligand enters the nanoparticle ligand shell, the polymerization reactionoccurs rapidly, before a second ligand exchange reaction can occur. Thepolymerization reaction will be favored through proximity effects, sopolymerizations that might be ‘poor’ polymerizations for making longpolymer chains will still sufficiently polymerize a ligand shell becauseit is a preoganized system due to bonding to nanoparticle 612.Polymerization may occur by anionic mechanisms (such as olefin,acetylene, or nucleophilic ring opening), radical mechanisms, carbonyladdition mechanisms (such as acetal-type polymerization), or cationicmechanisms.

Preferred suitable polymerizable moieties include —C═C—, —C═C—C═C—,—C≡C—, —C≡C—C≡C—, —CO— (ketone), —CS— (thioketone), —CSe—(selenoketone), acetal, thioacetal, epoxides, thiiranes (episulfides),and certain compounds with methyl activating groups, but any othersuitable polymerizable moieties known in the art may be advantageouslyemployed in the present invention. Possible polymerizable moieties alsoinclude two or more polymerizable groups, in order to provide a higherdegree of cross-linking with the nanoparticle shell.

Exposed terminating group Y 624 on stabilizing ligand 614 can be used tocontrol the solubility characteristics of the nanoparticle. Exposedterminating group Y 624 may be —CH₃, —COOH, —CONH₂, —COH, fluorinatedmethylene chains or other groups that provide desired solubility whilestill allowing for nanoparticle formation, or any other suitable groupknown in the art.

FIG. 6 further depicts ‘polymerizing’ ligand 640. Ligand 640 is designedto undergo place exchange reactions with nanoparticle system 610. Itshares many features with ligand 612 attached to nanoparticle 614. Themain difference is that polymerizing ligand 640 contains polymerizationinitiation moiety Z₁ 642, which is designed to initiate polymerizationonce it enters the nanoparticle ligand shell through a place exchangereaction. Polymerization initiating moiety Z₁ 642 is at the sameapproximate position with respect to the radius extending from thenanoparticle center as polymerizable moiety Z₁ 622, being surrounded bylinking methylene units n₁ 644 and m₁ 646. Polymerization initiatingmoiety Z₁ 642 may be —NH—, —S—, —Se—, —Te—, —PH—, —CO—, —COO—, CONH—,—PR₂, where R₂ is -methyl, —O, —NH, or any other suitable moiety knownin the art.

Polymerization may be initiated simply by the proximity of the newlyadded ‘polymerizing’ ligand, or by an external signal such as photons.Polymerization initiators such as Lewis basic groups like amines arefavorable, since they react mainly by a proximity effect. However,groups such as ketones may also be used, through photochemicalgeneration of radical pairs followed by capture of this excited statevia olefins, acetylenes, or other carbonyl compounds.

In the embodiment depicted in FIG. 6, polymerizing ligand 640 furthercontains attachment moiety X₁ 648 at one terminus, for attachment tonanoparticle 612. Typically, attachment moiety X₁ 648 is a Lewis basicmoiety, in order to provide stabilization of the metallic orsemiconductor nanoparticle 612, but any suitable moiety may be utilized.

Polymerization initiating ligand 640 contains linking moiety Y₁ 650 atthe other terminus, allowing for further reactions involving thenanoparticle. For instance, the nanoparticle may be attached to othermolecules that might themselves have several protected linkerchemistries embedded. Suitable functional linking moieties include, butare not limited to, —COOH—, —CONH₂, —COH, —CH₂OH, —CH₂OR₃ (where R₃ is aprotecting group), olefin, alkynyl, —COOR₄ (where R₄ is an alkyl or aprotecting group), and any group that will provide the desired linkingchemistry after the monofunctionalization reaction.

Assembly of nanoparticle building blocks. In the method of the presentinvention, the nanoparticle building blocks are assembled by successivechemical reactions, each reaction adding one or more nanoparticles bybuilding onto exposed, unprotected linker functionalities. Protectinggroups may optionally be used to control and organize growth. Severalkinds of linker chemistries, which may be chemically ‘orthogonal’ in thesense of having different, non-interfering, non-complementaryreactivities, may be used in the same system (See, e.g., U.S. Pat. No.5,310,869, Lewis et al. (1994)).

For example, alpha olefin functional groups with up to 18 carbons can beadvantageously employed in a hydrosilylation reaction (using catalyticplatinum, for example) in which a silicon hydride-functionalcross-linking species, such as a polymethylhydrosiloxane polymer,copolymer or terpolymer, or a polyfunctional polysilane, is employed.Likewise, many modern carbometallation reactions that createcarbon-carbon bonds can be performed under mild conditions that will notinterfere with a wide variety of functional groups, such as amide bonds.For example, an aryl bromide functionality can be reacted with an olefin(Heck coupling) or acetylene (Sonagashira coupling) in the presence of apalladium catalyst. Such reactions can be carried out under mildconditions in the presence of protected amines and carboxylic acids(protected or unprotected). Likewise, the amide-coupling chemistriesutilizing activating agents such as DCC (dicyclohexylcarbodiimide inorganic media), EDC (1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide, inaqueous media), BOP(benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate), and HBTU (o-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate) are compatible with thepresence of olefins, acetylenes, and aryl halides.

In one aspect, the present invention includes the creation of familiesof ligands that can be used to construct supramolecular entities, suchas nanoparticle chains, out of nanoparticle building blocks, such asligands and nanoparticle entities or precursors. In one embodiment,ligands are prepared that can wrap around an entire nanoparticle, orpart of a nanoparticle. The ligands are used as scaffolds upon which toplace suitable linking functionalities and, optionally, protectinggroups. Rigidity of the wrapping ligand allows for control andmaintenance of linker geometries. If two wrapping ligands are on onenanoparticle, these two ligands can be made sufficiently bulky toprevent the linker ‘arms’ of the ligands from interacting.

In various embodiments of the invention, ligand spheres may comprisetypical monodentate ligands normally used in synthesis of the givennanoparticle and/or custom-designed ligands containing linking chemistryfor assembly. In some embodiments, only linker ligands are present.Typically, two or more linker ligands are preferred on each nanoparticleor nanocluster, providing spatial and geometric control over theorientations of the linker moieties. Alternatively, it may be desirableto use one ligand designed to present several linker moieties atspatially separate locations on the ligand sphere. In some embodiments,nanoparticle/linker-ligand building blocks are obtained by directsynthesis using nanoparticle precursors, mixtures of standard ligands aswell as linker ligands, or only linking ligands. Wrapping linker ligandsmay optionally be used to control and/or stabilize the sizes ofnanoparticles.

In another aspect, the present invention features structures andsyntheses of the nanoparticle/linker ligand building blocks. In oneembodiment, nanoparticle precursors, mixtures of ligands, and linkermoiety precursors are directly used in the synthesis. The size ofnanoparticles may be optionally controlled and stabilized using wrappinglinker moieties. For example, hydrogen tetrachloroaurate may be mixedwith a reducing agent such as sodium borohydride, in the presence oflinking ligands and, optionally, certain inert ligands (e.g., alkylthiols or alkyl amines), as well as an appropriate solvent. Theresulting gold nanoparticles exhibit size selectivity and incorporatethe linking ligands. These nanoparticles can then be used to buildnanoparticle structures as described herein.

Synthesis may alternatively be accomplished by ligand exchange reactionsin solution using the linker moieties. In this procedure, analready-synthesized nanoparticle bearing stabilizing ligands issubjected to an excess of the desired linking ligand. Substitution ofthe linking ligand occurs, displacing the stabilizing ligand. In asimilar manner, synthesis may alternatively be accomplished by captureof electrostatically stabilized particles using the linker moieties.Synthesis may also be accomplished by capture of gas phase particlesusing the linker moieties. In any of the described methods of synthesis,the number of linking ligands per nanoparticle is crucial and can becontrolled by varying the synthetic conditions and/or by a number ofpurification means including, but not limited to, precipitation,chromatography, centrifugation, extraction, crystallization, andtitration.

In some embodiments, nanoparticle/linker-ligand building blocks areobtained by synthesis using place-exchange reactions in solution, usingthe linker ligands to replace inert stabilizing ligands around thenanoparticle with the desired linking ligands. In other embodiments, thebuilding blocks may be obtained by capture of electrostaticallystabilized particles using the linker ligands, possibly in combinationwith inert ligands. The nanoparticle/linker-ligand building blocks maybe employed in the synthesis of polymers, by using, for example,step-polymerization reactions or chain-polymerization reactions inconjunction with appropriate linker chemistries.

FIGS. 7A and 8-10 depict various exemplary ligand designs useful inpracticing the present invention. Ligands may have multiple ‘arms’ thatcan bind the nanoparticle through, for example, Lewis basic chelatinggroups. The linker ligands depicted typically have several thiols (fornoble metal nanoparticles) or other Lewis basic groups that provide thebond between the linking ligand and the nanoparticle. It is beneficialto have multiple bonds between the linking ligand and the nanoparticle.This multidentate effect, which is well known in organometallicchemistry, results in linking ligands that are held much more tightly tothe nanoparticle. This is essential, since these are the points ofattachment between two nanoparticles. The linking ligands must remain ona nanoparticle in order for stable multi-particle structures to beformed.

Ligands may also have one or more linker arms useful for connectingnanoparticles. The linker is used for hooking one nanoparticle toanother appropriately functionalized nanoparticle. The linking ligandsalso typically have methylene spacer units or the like, generally fiveto twenty, in order to provide sufficient length so that the other armcontaining the linker moiety can stick up out of the ligand sphere ofthe nanoparticle and be used for linking.

FIG. 7A depicts two exemplary ligand structures 710, 720 that can wrap agold nanoparticle and provide the functionality necessary for linkingparticles together. Since the ligands wrap around the particle, twolinking functionalities on the same particle will be separatedspatially. Molecular modeling shows that the structures in FIG. 7Apossess the appropriate structural features to allow the thiol ‘arms’722 of the molecules to bind to a gold nanoparticle surface, while thecarboxylate ‘linker arm’ 724 points out away from the nanoparticle core,allowing it to be used for linking chemistry. Using multiple attachmentpoints to the nanoparticle strengthens the ligand-particle bond due tothe multidentate effect. This adds stability to any nanoparticleensembles created.

These exemplary molecules are based on commercially available backbonestructures and can be synthesized by one knowledgeable in organicchemistry in a very straightforward manner. These ligands also possessenough steric bulk that they will take up a significant amount of ‘coneangle’ around the nanoparticle, where ‘cone angle’ refers to the solidangle taken up on the surface of a sphere surrounding the nanoparticlewhose outer surface coincides with the outer reaches of the ligandsphere around the particle. The total amount of cone angle around asphere is 4π, 12.57 steradians. Taking up cone angle around thenanoparticle helps ensure a certain amount of geometric restriction inthe case where there are two or more linking moieties on onenanoparticle. This is useful, since it will help ensure that thenanoparticle ensembles obey the desired geometric rules. For example, ifa straight polymer chain composed of nanoparticles is desired, thelinkers would be best situated 180 degrees from each other. In thatcase, if each linking ligand took up half of the total solid angle of asphere, then the linking ligands would be guaranteed to be 180 degreesapart. In a similar way, it is possible to design ligands that givelinking moieties oriented in trigonal, tetrahedral, bipyramidal, andetc. geometries.

FIG. 7B depicts the synthesis of some of the more easily synthesizedligands; more specifically, a synthetic scheme leading to two moleculesfor creating a bifunctional nanoparticle, again with the goal of takingup cone angle around the nanoparticle sphere. Since each of thesemolecules occupy a good amount of cone angle, and must displace severalthiols in order to occupy a spot on the nanoparticle, it is possible tocreate a difunctional nanoparticle building block, either throughstoichiometric ligand exchange and purification, or throughstoichiometric synthesis with inert ligands such as decanethiol. Byusing precursors A 740 or B 750, it is possible to generate a protectedamine or a protected carboxylic acid linking ligand in just a few steps.These are just examples of the many molecules that can be advantageouslyused in the present invention. They possess multidentate binding to ananoparticle for stability, and they have a linking moiety that issituated such that it can be accessible outside the ligand sphere of thenanoparticle.

FIG. 8 depicts a generic carbocycle moiety utilizable for the core ofthe ligand structure, having various attachment points. In general, alarge number of permutations are available. Ligands that may be used inpracticing the present invention include any ligands that have multiplearms, preferably of similar lengths, for binding to the nanoparticle,and at least one linker arm for attaching a linking moiety. In theexample depicted in FIG. 8, basic elements B 810 are connected in ring815 to any different basic element LB 820 by any number of methylenegroups l 830, m 840, n 850 or by other atoms. Attachment points forthiol or other Lewis basic chelating groups (for nanoparticlecoordination) can occur at any chemically accessible place on ring 815.The attachment point for the linking moiety can be at any of the ringatoms. Each segment of the cyclic structure can repeat an arbitrarynumber of times as well, providing any number of points of attachment tocentral ring 815.

FIGS. 9 and 10 depict the general structure of the ‘arms’ of a ligandthat may be employed in practice of the present invention, with FIG. 9depicting a generic chelating arm and FIG. 10 depicting a genericlinking arm. In FIG. 9, chelating element or functional group LB 910chelates to a nanoparticle's surface, thereby anchoring the ligand tothe particle. If desired, chelating element or functional group LB 910is also linked by any number of linking atoms m 915 to a linking orother functional group. In FIG. 10, linking moiety Link 1010 may be anyof the large number of possible chemistries that may be used to linkparticles together. Suitable examples include, but are not limited to,amide bond formation and metal-assisted carbon-carbon coupling, whichare orthogonal. If desired, linking moiety Link 1010 is also linked byany number of linking atoms m 1015 to a chelating element or functionalgroup, such as is shown in FIG. 9.

In one embodiment, cyclodextrins may advantageously be used onnanoparticles in order to create links between them. Cyclodextrins arecyclic oligosaccharides that are isolated from natural sources. FIG. 11depicts the B-cyclodextrin structure 1100 and the dimensions of thethree commercially available cyclodextrins. The three commerciallyavailable cyclodextrins have, respectively, 6 (α-cyclodextrin), 7(β-cyclodextrin), and 8 (γ-cyclodextrin) D-glucose units formed into acone-like ring and are quite inexpensive. The cyclodextrins have twosides named for the hydroxyl group numbering nomenclature in thecyclized D-glucose units 1110, all of which are oriented the same way.The 6′ side 1120 is the more narrow side of the cyclodextrin in thetypical cone representation shown in FIG. 11. The 2′ side 1130 is theother side of the cone, having a wider opening. Cyclodextrins have ahydrophobic cavity 1140 in the middle of them that is perfect forguest-host chemistry and hence the inner dimensions are used todetermine the size of a guest that can fit into the cyclodextrin innercavity. The classical guest-host interaction is the solubilization oforganics such as benzene or toluene in water through their interactionwith the inner cavity of a cyclodextrin molecule. Cyclodextrinsthemselves are highly water soluble, since the hydroxyl groups all pointaway from the inner cavity, and towards the solvent.

FIG. 12 depicts a linker structure involving the linking of twocyclodextrin structures 1210 using host-guest chemistry. By anchoringeach cyclodextrin 1210 to a nanoparticle 1220, it is possible to createa linkage between the nanoparticles by using a guest 1222-host 1224interaction to create a link 1228 between two cyclodextrins.Cyclodextrins are relatively easily functionalized fully on the 6′hydroxyl group and it is easy to fully convert the 6′ groups to thiols1230. Thiols 1230 can then be used as the bonding groups fornanoparticles 1220. As shown in FIG. 12, n is the number of thiols 1230bonding to each nanoparticle 1220, and n is 6, 7, or 8 depending on thecyclodextrin used. Due to the fact that each cyclodextrin has 6-8 thiols1230 to bind to nanoparticle 1220, it is a particularly strong bond.Also, due to the large disruption of a nanoparticle's ligand sphere andthe drastic change in the physical properties of the particle once acyclodextrin has bound, it is relatively easy to isolate nanoparticleshaving, for example, one or two (for instance) cyclodextrins attached.Bonds between derivatized nanoparticles may then be formed by adding adifunctional guest molecule, such as stilbene.

FIG. 13 depicts two cyclodextrins 1310 bound to a nanoparticle 1340 andlinkers LinkO 1320. Cyclodextrin chemistry serves as an example based onmore elaborate structures. By perthiolating cyclodextrin 1310 in the 6′position 1330, it is possible to attach cyclodextrin 1310 tonanoparticle 1340. As shown in FIG. 13, by functionalizing at the 2′position, which typically is a straightforward procedure, it is easy toattach linker arm LinkO 1330. Due to the size of cyclodextrin, there isonly room for two such ligands to fit on each 1.5-2 nm particle. Thistypically produces a nanoparticle with two oppositely-situatedfunctional linker arms. Cyclodextrins and molecules like them areextremely useful for the present invention, in that they allow a degreeof control over the cone angle that a linking ligand occupies. Controlof this cone angle allows for control of the geometry of the linkermoieties with respect to each other.

FIG. 14 depicts a cyclodextrin cage 1400 that can control nanoparticlesize and linker geometry. Cyclodextrin dimers, such as the one shown inFIG. 14, can be used to control both the size of the particle and theorientation of the linker arms 1420 attached on the 2′, 3′ sides 1430 ofthe cyclodextrin molecules 1436. Cyclodextrins 1436 can be perthiolatedat the 6′ side 1440, other than for the two 6′ positions 1450, 1460 usedin the making of the cyclodextrin dimer, allowing attachment ofnanoparticle 1480. By using a ligand such as the one shown in FIG. 14during a nanoparticle synthesis, control over nanoparticle size isrealized. In addition, by using this ligand on a smaller nanoparticle,the spatial arrangement of the linker arms is well controlled. Also,during a place exchange reaction, the bulk and multiple thiol bondsformed will be a significant perturbation of the nanoparticle ligandsphere, potentially making it possible to capture a singlyfunctionalized nanoparticle (with two linker arms) by simple reactionkinetics. Further, the physical properties change dramatically, makingphysical separation easier as well.

FIG. 15 depicts a cyclodextrin rotaxane 1510 designed to act as a spacerwithin the ligand sphere of a particle. Cyclodextrin rotaxane 1510provides control over the geometry between two linker arms 1520. Thenanoparticle 1530 provides the ‘stopper’ for the other end. To simplifysynthesis, unfunctionalized cyclodextrins may be used as spacers onmonodentate ligands possessing a linking functionality. The cyclodextrinserves to confine the linker arm to a certain orientation on theparticle with respect to another cyclodextrin ligand, and preventslinker arms of complementary functionalities on the same particle fromreacting in an unwanted manner. The ligand structure shown in FIG. 15 isdesigned to maximize the cone angle taken up by a linking ligand,therefore giving a favorable geometry when multiple linking ligands arepresent on one particle. Threading of cyclodextrins onto a nanoparticleusing a single thiol bond has been previously demonstrated (Liu, J. etal., Adv. Mater 12: 1381-1383 (2000)).

Assembly of nanoparticle chains. In general, arbitrary construction ofsupramolecular structures, such as nanoparticle chains, is preferred.The synthesis may be conducted by any appropriate method and in anyappropriate apparatus known in the art, but is preferably conducted inan apparatus much like a peptide synthesizer, using a feedstock ofnanoparticle building blocks. As previously discussed, the inventioninvolves the creation of families of ligands that can be used toconstruct nanoparticle chains out of nanoparticle building blocks, suchas ligands and nanoparticle entities or precursors. Stepwise synthesis,either manually or in an automated synthesizer, is used to build upstructures from the ligand/nanoparticle entities. Protecting groups canalso be utilized in the stepwise synthesis of the ligand/nanoparticleentities.

The synthesized supramolecular structures may have uniquecharacteristics such as anisotropic optical or electronic properties,non-linear optical polarizabilities, fluorescence, luminescence,waveguiding of photons or phonons, molecular computation, chiralcatalysis in chemical synthesis and/or chiral separations, orantibody-like properties of binding specific ligands. These propertiesmay arise due to the structure and composition of the supramolecularnanoparticle assemblies at multiple levels, e.g., primary, secondary,tertiary, and quaternary structural features, as in proteins.

The primary structure refers to the nanoparticle sequence, such asAu—Ag—CdS—TiO₂—Au—Au. Not only can the nanoparticle material be varied,but the structure of the linking ligands may also play a large role inthe resulting overall structure. Thus, the primary sequence also refersto the specific linking ligands used in the synthesis. For example,Au(L1)-Au(L2)-Au(L3), where L1, L2, L3 represent different linkingligands, may have a significantly different preference for folding thana sequence of Au(L3)-Au(L3)-Au(L2). The secondary, tertiary, andquaternary structures are analogous to the peptide definitions, withsecondary structure referring to structural motifs such as helices,tertiary structure referring to the conformation of an entire chain, andquaternary structure referring to the overall conformation of anassembly of chains.

Nanoparticle structures synthesized in accordance with the invention canexhibit folding patterns characterized by a primary, secondary,tertiary, and quaternary structural categorization, much like proteins.The nanoparticle supramolecular structures can be optimized bycombinatorial chemistry techniques or by automated parallel synthesis,with results being screened based on a desired property.

The folding can be expected to follow some basic principles, much likepeptides, such as, depending on the solvent used, folding due tohydrophilic/hydrophobic interactions to expose hydrophilic orhydrophobic sections to the solvent sphere. The characteristics of thefolding of nanoparticle assemblies depend on factors including thegeometric/dimensional parameters of the nanoparticles, size/length ofthe linking moiety chains, and overall colloidal sphere around eachnanoparticle. The folding can be determined without undueexperimentation and controlled, for example, by selecting the chemicalstructure (sequence) of the nanoparticle assembly/chain.

Nanoparticle assembly structures are built according to the presentinvention in a controlled, stepwise manner similar to peptide synthesis,which allows various techniques of parallel synthesis and combinatorialchemistry to be applied for the optimization of desirable properties.Hence, combinatorial techniques can be applied in combination withscreening techniques to develop optimal structures for, for example, an8-bit molecular adder, or a structure that binds a specificnanoparticle, or a chiral catalyst for hydrogenation. Additionally,florescent moieties may be attached to the linking ligands, therebyallowing monitoring of nanoparticle synthesis through spectroscopictechniques.

The linker moieties of the ligands are preferably designed for facile,high-yield coupling chemistry. Carboxylic acids and amines allow for theuse of pre-existing peptide chemistries, which have the benefit of yearsof experimental optimization. Other coupling chemistries may also beapplied. As discussed above, cyclodextrins may be advantageously used tocreate links between nanoparticles. Alternatively, a number ofcarbon-carbon coupling chemistries may be used to form linkages in amild chemical manner, such as Heck reactions and pi-allyl palladiumchemistry. In addition, by utilizing orthogonal protecting groupchemistry, non-interfering reaction paths of amide bond-formingchemistries can be utilized.

The apparatus and method of the present invention, therefore, providecontrolled synthesis of functionalized nanoparticles, nanoparticleassemblies, and nanoparticle chains. This is accomplished throughgeneralized coupling chemistries that allow buildup of arbitrary chainsof nanoparticles in a polymeric fashion, in part through the controlledincorporation of mono- to multifunctionality in the nanoparticle ligandsphere through incorporation of specifically designed chemicallyreactive sites. Each of the various embodiments described above may becombined with other described embodiments in order to provide multiplefeatures. Furthermore, while the foregoing describes a number ofseparate embodiments of the apparatus and method of the presentinvention, what has been described herein is merely illustrative of theapplication of the principles of the present invention. Otherarrangements, methods, modifications and substitutions by one ofordinary skill in the art are therefore also considered to be within thescope of the present invention, which is not to be limited except by theclaims that follow.

1. A method for connecting nanop articles into a multiple-nanoparticle assembly, comprising the steps of: providing a first nanoparticle having attached thereto at least one functional group of a first kind, wherein functional groups of the first kind do not react with one another; providing a second nanoparticle having attached thereto at least one functional group of a second kind, wherein functional groups of the second kind do not react with one another; and reacting at least one functional group of the first kind attached to a first nanoparticle with at least one functional group of the second kind attached to a second nanoparticle to cause connection between the first and second nanoparticles, forming a multiple-nanoparticle assembly.
 2. The method of claim 1, wherein the step of reacting is initiated by removing at least one protective group from a reactive functional group on at least one of the first or second nanoparticles.
 3. The method of claim 1, further comprising the step of performing additional functional group reactions in a step-wise manner until a structure of connected nanoparticles of a desired size and configuration is obtained.
 4. The method of claim 3, wherein the multiple-nanoparticle assembly is a nanoparticle chain.
 5. The method of claim 1, wherein the step of reacting at least one functional group of the first kind attached to a first nanoparticle with at least one functional group of the second kind attached to a second nanoparticle comprises a direct reaction between the functional group of the first kind and the functional group of the second kind.
 6. The method of claim 1, wherein the step of reacting at least one functional group of the first kind attached to a first nanoparticle with at least one functional group of the second kind attached to a second nanoparticle employs a linker component.
 7. The method of claim 1, wherein the at least one functional group of the first kind and the at least one functional group of the second kind comprise reactive chemical moieties.
 8. A multiple nanoparticle-based structure synthesized according to the method of claim
 3. 9. The multiple nanoparticle-based structure of claim 8, wherein the nanoparticle-based structure is a nanoparticle chain.
 10. A method for connecting nanoparticles into a multiple-nanoparticle assembly, comprising the steps of: providing a plurality of nanoparticles, each nanoparticle having attached thereto two or more functional groups, wherein the functional groups attached to any one nanoparticle do not react with one another; providing at least one linker component having at least two functional groups attached thereto, at least one linker component functional group being reactive to at least one of the functional groups attached to the nanoparticles; and contacting the nanoparticles and the linker component to cause connection between at least one pair of nanoparticles, forming a multiple-nanoparticle assembly.
 11. The method of claim 10, wherein the step of contacting comprises the step of removing at least one protective group from at least one reactive functional group on at least one of the nanoparticles.
 12. The method of claim 10, further comprising the step of making additional contacts between nanoparticles and linker components in a step-wise manner until a structure of connected nanoparticles of a desired size and configuration is obtained.
 13. The method of claim 12, wherein the nanoparticle assembly is a nanoparticle chain.
 14. The method of claim 10, wherein at least one functional group comprises a reactive chemical moiety.
 15. A multiple nanoparticle-based structure synthesized according to the method of claim
 12. 16. The multiple nanoparticle-based structure of claim 15, wherein the nanoparticle-based structure is a nanoparticle chain. 